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Cadherin 2 (CDH2, N-cadherin) and cadherin 13 (CDH13, T-cadherin, H-cadherin) affect the progress and prognoses of many cancers. However, their roles in adrenocortical carcinoma (ACC), a rare endocrine cancer, remain unclear. To decipher the roles of these proteins in ACC and to identify their regulatory targets, we analyzed their expression levels, gene regulatory networks, prognostic value, and targets in ACC, using various bioinformatic analyses. CDH2 was strongly downregulated and CDH13 was strongly upregulated in patients with ACC; the expression levels of these genes affected the prognosis. In 75 patients, the expression of CDH2 and CDH13 was altered by 8% and 5%, respectively. CDH2 and CDH13, as well as their neighboring genes, were predicted to form a complex network of interactions, mainly through coexpression and physical and genetic interactions. CDH2 and its altered neighboring genes (ANGs) mainly affect tumor-related gene expression, cell cycle, and energy metabolism. The regulation of tumor-related integrin function, gene transcription, metabolism, and amide and phospholipid metabolism are the main functions of CDH13 and its ANGs. MiRNA and kinase targets of CDH2 and CDH13 in ACC were identified. CDH13 expression in patients with ACC was positively associated with immune cell infiltration. Anti-PD1/CTLA-4/PD-L1 immunotherapy significantly downregulated the expression of CDH13 in patients with ACC. Foretinib and elesclomol were predicted to exert strong inhibitory effects on SW13 cells by inhibiting the expression of CDH2 and CDH13. These data indicate that CDH2 and CDH13 are promising targets for precise treatment of ACC and may serve as new biomarkers for ACC prognosis.

BackgroundCombining genetic risk factors and plasma fatty acids (FAs) can be used as an effective method of precision medicine to prevent hypertension risk.MethodsA total of 195,250 participants in the UK Biobank cohort were included in this study from 2006–2010. Polygenic risk scores (PRSs) were calculated for hypertension using single-nucleotide polymorphisms (SNPs). Concentrations of plasma FAs, including polyunsaturated fatty acids (PUFAs), monounsaturated fatty acids (MUFAs) and saturated fatty acids (SFAs), were tested by nuclear magnetic resonance. The Cox model was used to test for the main effects of PRS, different plasma FAs and their joint effects on hypertension. Relative excess risk due to interaction (RERI) and the attributable proportion due to interaction (AP) were used to test the additive interaction.ResultsPlasma PUFAs, n-3 PUFAs, MUFAs and SFAs were related to the risk of hypertension (PUFAs: HR, 0.878; 95% CI, 0.868–0.888; MUFAs: HR, 1.13; 95% CI, 1.123–1.150; SFAs: HR, 1.086; 95% CI, 1.074–1.098; n-3 PUFAs: HR, 0.984; 95% CI, 0.973–0.995). Moreover, an additive interaction was found between PRS and plasma FAs, which could contribute to an approximately 10–18% risk of hypertension, and the associations between high plasma MUFAs and a high PRS of hypertension were the strongest positive [RERI: 0.178 (95% CI: 0.062, 0.294), AP: 0.079 (95% CI: 0.027, 0.130)].ConclusionIncreased plasma MUFAs or SFAs and decreased plasma PUFAs or n-3 PUFAs were associated with hypertension risk, especially among people at high genetic risk.

BackgroundAlthough the emerging NGS-based assays, metagenomic next-generation sequencing (mNGS) and targeted next-generation sequencing (tNGS), have been extensively utilized for the identification of pathogens in pulmonary infections, there have been limited studies systematically evaluating differences in the efficacy of mNGS and multiplex PCR-based tNGS in bronchoalveolar lavage fluid (BALF) specimens.MethodsIn this study, 85 suspected infectious BALF specimens were collected. Parallel mNGS and tNGS workflows to each sample were performed; then, we comparatively compared their consistency in detecting pathogens. The differential results for clinically key pathogens were confirmed using PCR.ResultsThe microbial detection rates of BALF specimens by the mNGS and tNGS workflows were 95.18% (79/83) and 92.77% (77/83), respectively, with no significant difference. mNGS identified 55 different microorganisms, whereas tNGS detected 49 pathogens. The comparative analysis of mNGS and tNGS revealed that 86.75% (72/83) of the specimens were complete or partial concordance. Particularly, mNGS and tNGS differed significantly in detection rates for some of the human herpesviruses only, including Human gammaherpesvirus 4 (P

Abstract Objective This study aimed to investigate the role of cholesterol metabolism-related genes in nonfunctioning pituitary neuroendocrine tumors (NF-PitNETs) invading the cavernous sinus and analyze the differences in immune cell infiltration between invasive and noninvasive NF-PitNETs. Methods First, a retrospective analysis of single-center clinical data was performed. Second, the immune cell infiltration between invasive and noninvasive NF-PitNETs in the GSE169498 dataset was further analyzed, and statistically different cholesterol metabolism-related gene expression matrices were obtained from the dataset. The hub cholesterol metabolism-related genes in NF-PitNETs were screened by constructing machine learning models. In accordance with the hub gene, 73 cases of NF-PitNETs were clustered into two subtypes, and the functional differences and immune cell infiltration between the two subtypes were further analyzed. Results The clinical data of 146 NF-PitNETs were evaluated, and the results showed that the cholesterol (P = 0.034) between invasive and noninvasive NF-PitNETs significantly differed. After binary logistic analysis, cholesterol was found to be an independent risk factor for cavernous sinus invasion (CSI) in NF-PitNETs. Bioinformatics analysis found three immune cells between invasive and noninvasive NF-PitNETs were statistically significant in the GSE169498 dataset, and 34 cholesterol metabolism-related genes with differences between the two groups were obtained 12 hub genes were selected by crossing the two machine learning algorithm results. Subsequently, cholesterol metabolism-related subgroups, A and B, were obtained by unsupervised hierarchical clustering analysis. The results showed that 12 immune cells infiltrated differentially between the two subgroups. The chi-square test revealed that the two subgroups had statistically significance in the invasive and noninvasive samples (P = 0.001). KEGG enrichment analysis showed that the differentially expressed genes were mainly enriched in the neural ligand–receptor pathway. GSVA analysis showed that the mTORC signaling pathway was upregulated and played an important role in the two-cluster comparison. Conclusion By clinical data and bioinformatics analysis, cholesterol metabolism-related genes may promote the infiltration abundance of immune cells in NF-PitNETs and the invasion of cavernous sinuses by NF-PitNETs through the mTOR signaling pathway. This study provides a new perspective to explore the pathogenesis of cavernous sinus invasion by NF-PitNETs and determine potential therapeutic targets for this disease.

Background & Aims: Aflatoxin exposure increases the risk for hepatocellular carcinoma (HCC) in hepatitis B virus (HBV)-infected individuals, particularly males. We investigated sex-based differences in the HCC genome and antitumor immunity. Methods: Whole-genome, whole-exome, and RNA sequencing were performed on 101 HCC patient samples (47 males, 54 females) that resulted from HBV infection and aflatoxin exposure from Qidong. Androgen on the expression of aflatoxin metabolism-related genes and nonhomologous DNA end joining (NHEJ) factors were examined in HBV-positive HCC cell lines, and further tested in tumor-bearing syngeneic mice. Results: Qidong HCC differed between males and females in genomic landscape and transcriptional dysfunction pathways. Compared with females, males expressed higher levels of aflatoxin metabolism-related genes, such as AHR and CYP1A1, and lower levels of NHEJ factors, such as XRCC4, LIG4, and MRE11, showed a signature of up-regulated type I interferon signaling/response and repressed antitumor immunity. Treatment with AFB1 in HBV-positive cells, the addition of 2 nmol/L testosterone to cultures significantly increased the expression of aflatoxin metabolism-related genes, but reduced NHEJ factors, resulting in more nuclear DNA leakage into cytosol to activate cGAS-STING. In syngeneic tumor-bearing mice that were administrated tamoxifen daily via oral gavage, favorable androgen signaling repressed NHEJ factor expression and activated cGAS-STING in tumors, increasing T-cell infiltration and improving anti–programmed cell death protein 1 treatment effect. Conclusions: Androgen signaling in the context of genotoxic stress repressed DNA damage repair. The alteration caused more nuclear DNA leakage into cytosol to activate the cGAS-STING pathway, which increased T-cell infiltration into tumor mass and improved anti–programmed cell death protein 1 immunotherapy in HCCs.

In order to further grasp the contamination level of Alternaria toxins in red date, this study took commercially available red date and its products as the research objects, explored the extraction method of mycotoxins with QuChERS as the core and established ultra-high performance liquid chromatography-tandem mass spectrometry analysis technology for five kinds of Alternaria toxins in red dates, and analyzed the pollution level of Alternaria toxin in red jujube and its products. Results showed that the recovery of Alternaria toxins in solid samples by QuChERS method ranged from 74.89% to 98.04%, and in liquid samples by solid-phase extraction method ranged from 68.35% to 99.63% with the relative standard deviations less than 10%. After the determination of five Alternaria toxins in Jun-date from Aksu, Kashi and Hotan regions, two toxins, TeA and AOH, were detected. Among them, the TeA in Jun-date in Kashgar was the highest, reaching 5.12~10.76 μg/kg. Three Alternaria toxins, TeA, AOH and ALT, were detected in 11 kinds of products of red date, among which TeA in red date wine reached 127.08 μg/kg and AOH was detected only in amethyst date, with content ranging from 34.76 to 98.61 μg/kg. ALT was detected in freeze-dried red dates slices, fried red dates and amethyst date, with content ranging from 2.04 to 399.64 μg/kg. In this paper, a UPLC-MS/MS method was developed to meet the requirements for the determination of Alternaria toxins in date samples with different forms, it would provide a theoretical basis for the edible safety of red dates.

Abstract Background Toxoplasma gondii has been reported to be associated with higher mortality in patients with schizophrenia. This study aimed to explore the relationship between T. gondii infection and 25-year mortality based on data from the Third National Health and Nutrition Examination Survey (NHANES III) database. Methods Cases with serum T. gondii antibody test results were included in this study and the corresponding mortality dataset was obtained from the US National Center for Health Statistics (NCHS). Propensity score matching (PSM) was used to match age and sex between groups. The Cox proportional hazards model was used to evaluate the effect of T. gondii infection on mortality. Results A total of 14,181 cases were included in the analysis, of which 3831 (27.0%) were seropositive for T. gondii antibody. The median follow-up time of the whole cohort was 22.5 (interquartile range 16.3, 24.5) years. A total of 5082 deaths were observed in this cohort, a mortality rate of 35.8%. All-cause mortality was significantly higher in the seropositive group than in the seronegative group (50.0% vs 30.6%, P

Objective: The aim of this study was to evaluate the incidence and duratio n of delayed hyponatremia and to assess the factors influencing the developme nt of delayed hyponatremia after transsphenoidal surgery (TSS) in pituitary a denomas. Methods: We retrospectively analyzed the clinical data of patients with pituitary adenoma who underwent TSS. Univariable and multivariable statistics wer e carried out to identify factors independently associated with the occurrence of delayed hyponatremia. Results: Of the 285 patients with pituitary adenoma who underwent micro scopic TSS, 44 (15.4%) developed postoperative-delayed hyponatremia and 241 (84.6%) did not. The onset of delayed hyponatremia occurred an average of 5.84 d ays post-surgery and persisted for an average of 5.36 days. Logistic regression anal ysis showed the highest risk of delayed hyponatremia in patients with significant change in tumor cavity height (odds ratio (OR), 1.158; 95% CI, 1.062, 1.262; P = 0.001), preoperative hypothalamus– pituitary–thyroid axis hypofunction (OR, 3.112; 95% CI, 1.481, 6.539; P = 0.003), and significant difference in blood sodium levels before and 2 days a fter TSS (OR, 1.101; 95% CI, 1.005, 1.206; P = 0.039). Conclusions: Preoperative hypothyroidism, difference in blood sodium levels before and 2 days after TSS, and the change in tumor cavity height after T SS played important roles in predicting postoperative-delayed hyponatremia onset in patients with pituitary adenomas.

BackgroundBromodomain and extracellular terminal (BET) family (including BRD2, BRD3, and BRD4) is considered to be a major driver of cancer cell growth and a new target for cancer therapy. Currently, more than 30 targeted inhibitors have shown significant inhibitory effects against various tumors in preclinical and clinical trials. However, the expression levels, gene regulatory networks, prognostic value, and target prediction of BRD2, BRD3, and BRD4 in adrenocortical carcinoma (ACC) have not been fully elucidated. Therefore, this study aimed to systematically analyze the expression, gene regulatory network, prognostic value, and target prediction of BRD2, BRD3, and BRD4 in patients with ACC, and elucidated the association between BET family expression and ACC. We also provided useful information on BRD2, BRD3, and BRD4 and potential new targets for the clinical treatment of ACC.MethodsWe systematically analyzed the expression, prognosis, gene regulatory network, and regulatory targets of BRD2, BRD3, and BRD4 in ACC using multiple online databases, including cBioPortal, TRRUST, GeneMANIA, GEPIA, Metascape, UALCAN, LinkedOmics, and TIMER.ResultsThe expression levels of BRD3 and BRD4 were significantly upregulated in ACC patients at different cancer stages. Moreover, the expression of BRD4 was significantly correlated with the pathological stage of ACC. ACC patients with low BRD2, BRD3, and BRD4 expressions had longer survival than patients with high BRD2, BRD3, and BRD4 expressions. The expression of BRD2, BRD3, and BRD4 was altered by 5%, 5%, and 12% in 75 ACC patients, respectively. The frequency of gene alterations in the 50 most frequently altered BRD2, BRD3, and BRD4 neighboring genes in these ACC patients were ≥25.00%, ≥25.00%, and ≥44.44%, respectively. BRD2, BRD3, and BRD4 and their neighboring genes form a complex network of interactions mainly through co-expression, physical interactions, and shared protein domains. Molecular functions related to BRD2, BRD3, and BRD4 and their neighboring genes mainly include protein-macromolecule adaptor activity, cell adhesion molecule binding, and aromatase activity. Chemokine signaling pathway, thiamine metabolism, and olfactory transduction were found to be enriched as per the KEGG pathway analysis. SP1, NPM1, STAT3, and TP53 are key transcription factors for BRD2, BRD4, and their neighboring genes. MiR-142-3P, miR-484, and miR-519C were the main miRNA targets of BRD2, BRD3, BRD4, and their neighboring genes. We analyzed the mRNA sequencing data from 79 patients with ACC and found that ZSCAN12, DHX16, PRPF4B, EHMT1, CDK5RAP2, POMT1, WIZ, ZNF543, and AKAP8 were the top nine genes whose expression were positively associated with BRD2, BRD3, and BRD4 expression. The expression level of BRD2, BRD3, and BRD4 positively correlated with B cell and dendritic cell infiltration levels. BRD4-targeted drug PFI-1 and (BRD2, BRD3, and BRD4)-targeted drug I-BET-151 may have good inhibitory effects on the SW13 cell line.ConclusionsThe findings of this study provide a partial basis for the role of BRD2, BRD3, and BRD4 in the occurrence and development of ACC. In addition, this study also provides new potential therapeutic targets for ACC, which can serve as a reference for future basic and clinical research.

Background: Serine hydroxymethyltransferase (SHMT) is a serine-glycine-one-carbon metabolic enzyme in which SHMT1 and SHMT2 encode the cytoplasmic and mitochondrial isoenzymes, respectively. SHMT1 and SHMT2 are key players in cancer metabolic reprogramming, and thus are attractive targets for cancer therapy. However, the role of SHMT in patients with renal cell carcinoma (RCC) has not been fully elucidated. We aimed to systematically analyze the expression, gene regulatory network, prognostic value, and target prediction of SHMT1 and SHMT2 in patients with kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), and kidney renal papillary cell carcinoma (KIRP); elucidate the association between SHMT expression and RCC; and identify potential new targets for clinical RCC treatment. Methods: Several online databases were used for the analysis, including cBioPortal, TRRUST, GeneMANIA, GEPIA, Metascape, UALCAN, LinkedOmics, and TIMER. Results: SHMT1 and SHMT2 transcript levels were significantly down- and upregulated, respectively, in patients with KICH, KIRC, and KIRP, based on sample type, individual cancer stage, sex, and patient age. Compared to men, women with KIRC and KIRP showed significantly up- and downregulated SHMT1 transcript levels, respectively. However, SHMT2 transcript levels were significantly upregulated in the patients mentioned above. KIRC and KIRP patients with high SHMT1 expression had longer survival periods than those with low SHMT1 expression. In patients with KIRC, the findings were similar to those mentioned above. However, in KICH patients, the findings were the opposite regarding SHMT2 expression. SHMT1 versus SHMT2 were altered by 9% versus 3% (n = 66 KICH patients), 4% versus 4% (n = 446 KIRC patients), and 6% versus 7% (n = 280 KIRP patients). SHMT1 versus SHMT2 promoter methylation levels were significantly up- and downregulated in patients with KIRP versus KIRC and KIRP, respectively. SHMT1, SHMT2, and their neighboring genes (NG) formed a complex network of interactions. The molecular functions of SHMT1 and its NG in patients with KICH, KIRC, and KIRP, included clathrin adaptor, metalloendopeptidase, and GTPase regulator activities; lipid binding, active transmembrane transporter activity, and lipid transporter activity; and type I interferon receptor binding, integrin binding, and protein heterodimerization, respectively. Their respective Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were involved in lysosome activity, human immunodeficiency virus 1 infection, and endocytosis; coronavirus disease 2019 and neurodegeneration pathways (multiple diseases); and RIG-I-like receptor signaling pathway, cell cycle, and actin cytoskeleton regulation. The molecular functions of SHMT2 and its NG in patients with KICH, KIRC, and KIRP included cell adhesion molecule binding and phospholipid binding; protein domain-specific binding, enzyme inhibitor activity, and endopeptidase activity; and hormone activity, integrin binding, and protein kinase regulator activity, respectively. For patients with KIRC versus KIRP, the KEGG pathways were involved in cAMP and calcium signaling pathways versus microRNAs (MiRNAs) in cancer cells and neuroactive ligand-receptor interactions, respectively. We identified the key transcription factors of SHMT1 and its NG. Conclusions: SHMT1 and SHMT2 expression levels were different in patients with RCC. SHMT1 and SHMT2 may be potential therapeutic and prognostic biomarkers in these patients. Transcription factor (MYC, STAT1, PPARG, AR, SREBF2, and SP3) and miRNA (miR-17-5P, miR-422, miR-492, miR-137, miR-30A-3P, and miR-493) regulations may be important strategies for RCC treatment.

CRF07_BC is one of the most prevalent HIV-1 strains in China, which contributes over one-third of the virus transmissions in the country. In general, CRF07_BC is associated with slower disease progression, while the underlying mechanisms remain unclear. Our study focused on envelope proteins (Env) and its V3 loop which determine viral binding to co-receptors during infection of cells. We studied a large dataset of 3,937 env sequences in China and found that CRF07_BC had a unique profile of predominantly single CCR5 tropism compared with CCR5 and CXCR4 dual tropisms in other HIV-1 subtypes. The percentages of the CXCR4-tropic virus in B (3.7%) and CRF01_AE (10.4%) infection are much higher than that of CRF07_BC (0.1%), which is supported by median false-positive rates (FPRs) of 69.8%, 25.5%, and 13.4% for CRF07_BC, B, and CRF01_AE respectively, with a cutoff FPR for CXCR4-tropic at 2%. In this study, we identified the first pure CXCR4-tropic virus from one CRF07_BC-infected patient with an extremely low CD4+T cell count (7 cells/mm3). Structural analysis found that the V3 region of this virus has the characteristic 7T and 25R and a substitution of conserved “GPGQ” crown motif for “GPGH”. This study provided compelling evidence that CRF07_BC has the ability to evolve into CXCR4 strains. Our study also lay down the groundwork for studies on tropism switch, which were commonly done for other HIV-1 subtypes, for the long-delayed CRF07_BC.

BackgroundOAS1 expression in pancreatic cancer has been confirmed by many studies. However, the prognostic value and mechanism of OAS1 in pancreatic cancer have not been analyzed.MethodsThe RNA-seq in pancreatic cancer were obtained by UCSC XENA and GEO database. In addition, immunohistochemical validation and analysis were performed using samples from the 900th hospital. The prognosis of OAS1 was evaluated by timeROC package, Cox regression analysis, and Kaplan-Meier survival curves. Then, the main functional and biological signaling pathways enrichment and its relationship with the abundance of immune cells were analyzed by bioinformatics.ResultsOAS1 was highly expressed in pancreatic cancer compared with normal pancreatic tissue. High OAS1 expression was associated with poor overall survival (p

Objective To evaluate the association between inflammation-related markers, modified Glasgow Prognostic Score (mGPS) and Glasgow Prognostic Score (GPS), and survival outcome and recurrence risk in patients with hepatocellular carcinoma (HCC) after treatment.Design Systematic reviews and meta-analysis of cohort studies.Date sources Embase, Scopus, Web of Science and PubMed were searched through 10 March 2021.Eligibility criteria We included cohort studies that assessed the effect of pretreatment mGPS/GPS levels on survival outcomes in patients with HCC.Data extraction and synthesis Two researchers independently selected the data and reached a consensus. In case of disagreement, a third researcher was required to assist. The HRs and 95% CIs were used as the effect size indexes. Newcastle-Ottawa Scale was used to assess risk of bias and quality assessment of the included studies.Results The meta-analysis included 23 studies, most of which were retrospective. Participants were grouped according to the score of mGPS/GPS. When analysed into two groups (1/2 vs 0), the results showed that patients with a mGPS/GPS of 1 or 2 had poorer overall survival (OS) than those with a score of 0 (both p

The quantitative identification of water sources is an important prerequisite for objectively evaluating the degree of aquifer interference and predicting the production potential of coalbed methane (CBM) wells. However, this issue has not been solved yet, and water sources are far from being completely understood. Stable water isotopes are important carriers of water source information, which can be used to identify the water sources for CBM wells. Taking the Zhijin block in the Western Guizhou Province as an example, the produced water samples were collected from CBM wells. The relationships between the stable isotopic compositions of the produced water samples and the production data were quantitatively analyzed. The following main conclusions were obtained. (1) The δD and δ18O values of the produced water samples were between −73.37‰ and −27.56‰ (average −56.30‰) and between −11.04‰ and −5.93‰ (average −9.23‰), respectively. The water samples have D-drift characteristics, showing the dual properties of atmospheric precipitation genesis and water–rock interaction modification of the produced water. An index d was constructed to enable the quantitative characterization of the degree of D-drift of the produced water. (2) The stable isotopic compositions of produced water showed the control of the water sources on the CBM productivity. The probability of being susceptible to aquifer interference increased with the increasing span of the producing seam combination, reflected in the lowering δD and δ18O values and the decreasing gas productivity. (3) Three types of water, namely, static water, dynamic water, and mixed water, were identified. The characteristic values of the isotopic compositions of the static and dynamic water were determined. Accordingly, a quantitative identification method for the produced water sources was constructed, based on their stable isotopic compositions. The identification results have a clear correlation with the gas production, and the output of the static water contributes to the efficient CBM production. The method for the quantitative identification of the water sources proposed in this study, can help to improve the CBM development efficiency and optimize the drainage technology.

Background: Pyrroline-5-carboxylate reductase (PYCR) includes three human genes encoding three isozymes, PYCR1, PYCR2, and PYCR3 (or PYCRL), which facilitate the final step in the conversion of glutamine to proline. These genes play important roles in regulating the cell cycle and redox homeostasis as well as promoting growth signaling pathways. Proline is abnormally upregulated in a variety of cancers, and as the last key enzyme in proline production, PYCR plays an integral role in promoting tumorigenesis and cancer progression. However, its role in patients with kidney renal papillary cell carcinoma (KIRP) has not been fully elucidated. In this study, we aimed to systematically analyze the expression, gene regulatory network, prognostic value, and target prediction of PYCR in patients with KIRP, elucidate the association between PYCR expression and KIRP, and identify potential new targets for the clinical treatment of KIRP. Methods: We systematically analyzed the expression, prognosis, gene regulatory network, and regulatory targets of PYCR1, PYCR2, and PYCRL in KIRP using multiple online databases including cBioPortal, STRING, MethSurv, GeneMANIA, Gene Expression Profiling Interactive Analysis (GEPIA), Metascape, UALCAN, LinkedOmics, and TIMER. Results: The expression levels of PYCR1, PYCR2, and PYCRL were considerably upregulated in patients with KIRP based on sample type, sex, age, and individual cancer stage. PYCR1 and PYCR2 transcript levels were markedly upregulated in females than in males, and patients aged 21–40 years had higher PYCR1 and PYCR2 transcript levels than those in other age groups. Interestingly, PYCR2 transcript levels gradually decreased with age. In addition, the expressions of PYCR1 and PYCR2 were notably correlated with the pathological stage of KIRP. Patients with KIRP with low PYCR1 and PYCR2 expression had longer survival than those with high PYCR1 and PYCR2 expression. PYCR1, PYCR2, and PYCRL were altered by 4%, 7%, and 6%, respectively, in 280 patients with KIRP. The methylation levels of cytosine-phosphate-guanine (CpG) sites in PYCR were markedly correlated with the prognosis of patients with KIRP. PYCR1, PYCR2, PYCRL, and their neighboring genes form a complex network of interactions. The molecular functions of the genes, as demonstrated by their corresponding Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, included calcium channel activity, phospholipid binding, RNA polymerase II-specificity, and kinase and GTPase-regulatory activities. PYCR1, PYCR2, and PYCRL targeted miR-21, miR-221, and miR-222, resulting in a better prognosis of KIRP. We analyzed mRNA sequencing data from 290 patients with KIRP and found that ADA, NPM3, and TKT were positively associated with PYCR1 expression; PFDN2, JTB, and HAX1 were positively correlated with PYCR2 expression; SHARPIN, YDJC, and NUBP2 were positively correlated with PYCRL expression; PYCR1 was positively correlated with B cell and CD8+ T-cell infiltration levels; macrophage infiltration was negatively correlated with PYCR2 expression; and PYCRL expression was negatively correlated with B-cell, CD8+ T cell, and dendritic cell infiltration levels. Conclusions: PYCR1, PYCR2, and PYCRL may be potential therapeutic and prognostic biomarkers for patients with KIRP. The regulation of microRNAs (miRNAs), including miR-21, miR-221, and miR-222, may prove an important strategy for KIRP treatment.

Renal tubular injury is considered as the main pathological feature of acute kidney injury (AKI), and mitochondrial dysfunction in renal tubular cells is implicated in the pathogenesis of AKI. The estrogen-related receptor γ (ERRγ) is a member of orphan nuclear receptors which plays a regulatory role in mitochondrial biosynthesis, energy metabolism and many metabolic pathways. Online datasets showed a dominant expression of ERRγ in renal tubules, but the role of ERRγ in AKI is still unknown. In the present study, we investigated the role of ERRγ in the pathogenesis of AKI and the therapeutic efficacy of ERRy agonist DY131 in several murine models of AKI. ERRγ expression was reduced in kidneys of AKI patients and AKI murine models along with a negative correlation to the severity of AKI. Consistently, silencing ERRγ in vitro enhanced cisplatin-induced tubular cells apoptosis, while ERRγ overexpression in vivo utilizing hydrodynamic-based tail vein plasmid delivery approach alleviated cisplatin-induced AKI. ERRγ agonist DY131 could enhance the transcriptional activity of ERRγ and ameliorate AKI in various murine models. Moreover, DY131 attenuated the mitochondrial dysfunction of renal tubular cells and metabolic disorders of kidneys in AKI, and promoted the expression of the mitochondrial transcriptional factor A (TFAM). Further investigation showed that TFAM could be a target gene of ERRγ and DY131 might ameliorate AKI by enhancing ERRγ-mediated TFAM expression protecting mitochondria. These findings highlighted the protective effect of DY131 on AKI, thus providing a promising therapeutic strategy for AKI. [ABSTRACT FROM AUTHOR]

Recently, many authors have studied degenerate Bernoulli and degenerate Euler polynomials. Let [Formula: see text] be a random variable whose moment generating function exists in a neighbourhood of the origin. The aim of this paper is to introduce and study the probabilistic extension of degenerate Bernoulli and degenerate Euler polynomials, namely the probabilistic degenerate Bernoulli polynomials associated with [Formula: see text] and the probabilistic degenerate Euler polynomials associated with [Formula: see text]. Also, we intoduce the probabilistic degenerate [Formula: see text]-Stirling numbers of the second associated with [Formula: see text] and the probabilistic degenerate two variable Fubini polynomials associated with [Formula: see text]. We obtain some properties, explicit expressions, recurrence relations and certain identities for those polynomials and numbers. As special cases of [Formula: see text], we treat the gamma random variable with parameters [Formula: see text], the Poisson random variable with parameter [Formula: see text], and the Bernoulli random variable with probability of success [Formula: see text].

In this paper, we study the degenerate unipoly-Dedekind sums rising from the type 2 degenerate unipoly Bernoulli functions and degenerate unipoly-Bernoulli functions of arbitrary indices, respectively.

Recently, degenerate harmonic numbers and degenerate hyperharmonic numbers are introduced by Kim-Kim. In this paper, we study the series involving the degenerate harmonic numbers and degenerate Stirling numbers and investigate those properties.

BackgroundThe ETER701 trial assessed the efficacy and safety of benmelstobart combined with anlotinib plus etoposide/cisplatin (BEN-AL-EC) as a first-line therapy for extensive-stage small-cell lung cancer (ES-SCLC). Results indicated that BEN-AL-EC, when compared with placebo in combination with etoposide/cisplatin (PLB-EC), significantly enhanced both progression-free and overall survival rates, while demonstrating an acceptable safety profile among patients with ES-SCLC. However, BEN-AL-EC is expensive, necessitating its cost-effectiveness analysis.MethodsA Markov model with three health states was developed to evaluate the cost-effectiveness of BEN-AL-EC, AL-EC and PLB-EC for the treatment of ES-SCLC from the perspective of the Chinese healthcare system. Drug costs were derived from national tender prices, whereas other costs and utility values were derived from published literature. The key outcomes assessed included total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). Sensitivity analyses, including one-way and probabilistic analyses, were performed to assess the robustness of the model.ResultsThe total cost of BEN-AL-EC was $55,117.42, yielding 1.09 QALYs, whereas that of PLB-EC was $15,238.15, yielding 0.71 QALYs. The ICER of BEN-AL-EC compared with PLB-EC was $106,249.42 per QALY gained. At a willingness-to-pay threshold of $38,133 per QALY, BEN-AL-EC had a 0% probability of being cost-effective relative to PLB-EC. The key parameters influencing these outcomes included utility values for PFS, the cost of benmelstobart, and the discount rate.ConclusionFrom the perspective of the Chinese healthcare system, BEN-AL-EC as a first-line treatment for ES-SCLC is unlikely to be cost-effective when compared with PLB-EC.